Gene Therapy of Severe Inherited Photoreceptor Diseases due to Mutations in Large Genes

Inherited retinal diseases (IRD) are a major cause of worldwide, untreated blindness. The majority of cases are due to mutations in genes expressed in retinal photoreceptor cells (PR).

Recently, our lab group has contributed to the finding that gene therapy using adeno-associated viral vectors (AAV) is safe and effective in patients with rare forms of inherited childhood blindness,,and this bodes well for treatment of the more common photoreceptor-specific IRD. Several genes expressed in PR and involved in IRD are larger in size than what is tolerated by AAV vectors. While other gene therapy vectors derived from either adenovirus (Ad) or lentiviruses (LV) have larger cargo capacities than AAV, they do not effectively infect have PR.

Our goal is to overcome the challenge of transferring large genes to PR in order to develop therapies for common IRD. We are using a system to increase AAV cargo capacity based on dual AAV vectors, each containing one of the two halves of a large gene reconstituted upon co-infection of target cells and intermolecular AAV joining. The results from this project may provide novel treatment options for common severe blinding conditions.

We have shown that single intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-ARSB in MPS VI cats results in long-term ARSB expression, the clearance of GAG storage,the improvement of long bone length, the reduction of heart valve thickness, and the improvement of spontaneous mobility. These promising results prompted us to plan a clinical trial to investigate this strategy in MPS VI patients.

Vector Core

Gene transfer vectors are widely used in preclinical studies in disease animal models and as research tools to achieve gene transfer in vitro and in vivo. There is no single vector that is adequate for all applications, and the gene transfer vector has to be carefully chosen depending on disease, targeted cell type, number of treatments required, and the size and nature of the gene to be delivered.

Viral vectors were the first to be developed, as they exploit the natural property of viruses to transfer their genetic material into the nucleus of infected cells. Vectors derived from DNA viruses do not usually integrate into the host genome and are not replicated at cell division. Therefore, long-term transgene expression from DNA virus-derived vectors is restricted to post-mitotic cells.

Our Vector Core is devoted to providing research grade adeno-associated viral (AAV) vector and adenoviral (Ad) vectors to TIGEM researchers at low cost with a short turn-around time.